The present invention relates to a magnetic particle manipulator and separator, and more particularly, to a magnetic particle manipulator and separator which is fully integrated on a silicon wafer. The magnetic particle manipulator and separator is comprised of a plurality of integrated inductive components which are located on both sides of a fluid channel formed in the integrated circuit. In operation, the inductive components generate magnetic fields which cause magnetic particles suspended in a fluid passing through the fluid channel to be separated from the fluid.
Prior to the present invention, macro-scale magnetic particle separators have been realized using permanent magnets. One such conventional magnetic particle separator utilizes an array of arbitrarily positioned, rectangular, rare-earth permanent magnets. Generally, in order to achieve a magnetic field gradient which is sufficient to separate the particles, quadrupole or multipole permanent magnet arrangements are adopted and ferromagnetic wires are also introduced to generate the required magnetic gradient in an otherwise uniform magnetic field. When the magnetic particles suspended in a solution are subjected to the field, the magnetic forces produced by the magnets cause the particles to migrate and coalesce on to the magnetic poles or the ferromagnetic wires.
Another type of conventional magnetic particle separator comprises a microtiter well for holding a buffer solution. Permanent magnets of opposite polarity are located within the well opposite each other. A fluid suspension with a specific ferrofluid reagent is pipetted into the microtiter well. A T-shaped frame holds removable ferromagnetic wires which are in contact with the solution. Cells specifically labeled with the ferrofluid reagents or magnetic particles are pulled onto the wires and, thus, are immobilized. The microtiter well is then lowered and subsequent wash steps can be performed on the immobilized cells (which are still in the magnetic field) using fresh buffer.
Generally, these conventional separators require hybrid-type components such as T-shaped loop holders, wires, permanent magnets, and yoke frames to construct the separators, which consequently increases the cost of the device. In addition, these separators usually involve somewhat complicated as well as time consuming separation steps. The present invention provides an integrated micromachined particle manipulator and separator which can be produced at a lower cost than conventional separators and which provides relative ease of handling. Since the magnetic particle manipulator and separator of the present invention is comprised as an integrated circuit, it is amenable to mass production. Other advantages of the present invention are, for example, design flexibility, compactness, and electrical control. Generally, the areas of the present invention include biological cell fractionation, enzyme immobilization, magnetic affinity chromatography, immunoassay, and extraction of impurities by absorption of materials onto magnetic particles.
The following patents disclose various type of prior art magnetic particle separators. Zborowski et al., U.S. Pat. No. 5,053,344, discloses a magnetic field separation system having a flow chamber comprised of first and second optically transparent slides mounted so as to define a generally planar fluid pathway. The flow chamber is oriented to promote fluid flow therethrough by a combination of gravitational and capillary action. Permanent magnets constitute a magnet means for separating sensitized particles in a biological fluid.
Carew, U.S. Pat. No. 5,123,901, discloses a method for removing or separating pathogenic or toxic agents from body fluids in which the pathogenic or toxic agent is flowed into a mixing coil along with a plurality of paramagnetic beads for marking the pathogenic agent. The mixture is then passed through a magnetic separator having a separation chamber. The separator is provided with a graded magnetic field along the length of the separation chamber. The magnetic field causes the paramagnetic beads with bound pathogenic agent to adhere magnetically to the wall of the separator.
Aubry, Jr., et al., U.S. Pat. No. 3,608,718, discloses a magnetic separator method and apparatus. The apparatus consists of a tubular element having a first baffle which divides the tube inlet into a feed inlet for receiving fluidized material and a surrounding coaxial passage for receiving wash fluid, and a second baffle spaced downstream from the first baffle for dividing the tube outlet into a tailings discharge passage and a surrounding coaxial concentrate discharge passage. Magnetic and magnetizable particles are attracted outwardly between the baffles by way of a radial magnetic field applied in the tube from a source surrounding the tube.
Christensen, U.S. Pat. No. 4,769,130, discloses a high-gradient magnetic separator for filtering weekly-magnetic particles from a fluid in which they are suspended. The fluid is caused to flow through a separation chamber arranged in a gap formed between a pair of opposed poled surfaces of a pair of separate permanent magnetic devices connected with a closed magnetic circuit which includes yoke members. The separator is designed as a large scale high-intensity and high-gradient separator for industrial applications operating without external power supply. Other examples of magnetic particle separators are disclosed in Muller-Ruchholtz et al., U.S. Pat. No. 4,738,773, Kronick, U.S. Pat. No. 4,375,407, and Yen et al., U.S. Pat. No. 4,219,411.
It is apparent that none of the foregoing patents propose an integrated particle separator. The present invention provides a fully integrated magnetic particle manipulator and separator which is fabricated on a silicon wafer and which includes integrated inductive components for generating the required magnetic fields. In the past, inductors generally were not used in integrated circuits due to the inability to achieve high enough inductor values to be useful in circuit design. Integrated circuit inductors have been used effectively in microwave circuits which operate at frequencies in the GHz range. For example, spiral inductors have been used in GaAs integrated circuits developed for receiving direct-broadcast satellite television signals. More recently, planar inductors have been implemented on chips which have applications in filters, sensors, AC/DC converters, and magnetic microactuators. Such structures have been fabricated using multilevel metal schemes to "wrap" a wire around a magnetic core or air core, but they tend to have relatively high resistance due to the fact that two interconnect vias per turn are required to realize the device.
In accordance with the present invention, the roles of the conductor wire and magnetic core in conventional inductors have been interchanged and the effect produced by the conventional inductors has been achieved by using a multilevel magnetic core which is "wrapped" around a planar conductor. This structure has the advantage that a relatively short, planar conductor is used, thus reducing total conductor resistance. In addition, this geometry has at least two advantages over the planar spiral-type geometry. First, the length of the conductor wire necessary to achieve the same number of turns is shorter than that of spiral conductors, which results in smaller conductor series resistance. Second, since the magnetic cores are tightly linked with the conductor coils, the leakage flux is relatively low, resulting in relatively high inductance. This meander-type integrated inductor and all of the other components of the magnetic particle separator have been fully integrated on a silicon wafer, as described in detail below.